"Over time, the aggregate risk of completed suicide is likely to be much lower with treatment than without treatment," says Steve Hyman, former director of the National Institute of Mental Health.

The recent controversy surrounding antidepressant drugs and suicide risk has raised important questions about the risks and benefits of treating depression, the most common mental disorder and the leading cause of disability worldwide. The debate also has underscored a troubling fact about depression treatment: beyond drugs such as fluoxetine (Prozac) and sertraline (Zoloft), there is a paucity of therapeutic options. And the situation is not likely to change any time soon. Selective serotonin reuptake inhibitors, or SSRIs, have been the mainstay of depression therapy since fluoxetine was approved in 1988. SSRIs act to increase the amount of serotonin, a brain chemical involved in mood regulation, available to nerve cells. Some newer antidepressants target a different neurotransmitter called norepinephrine or act on both norepinephrine and serotonin. These drugs revolutionized depression treatment, offering hope to millions of people in the form of once-daily pills. Drug companies rode the wave, churning out copycat or slightly tweaked formulas, heavily promoting the drugs to patients and doctors, and racking up billions in sales. But things have changed in recent years. In 2004, the Food and Drug Administration (FDA) required drug makers to include a “black box” warning on all antidepressant labels to reflect new evidence that the drugs moderately increase suicide and suicidal thinking in children and adolescents. After the FDA’s action, prescriptions for the drugs plummeted 20 to 30 percent, according to different estimates. In December 2006, the FDA determined that the drugs carried a higher risk of suicide for young adults up to age 25, but not for older adults. As with children, the greatest risk is during the initial weeks of treatment, though it is not clear why. The FDA issued a public health advisory about the risk and is expected to require updated labeling to reflect the new findings. Widely reported in the press, the findings and drop in prescriptions have left many psychiatric and public health experts worried that people will abandon their medications or that doctors will stop prescribing the drugs altogether. Untreated depression, especially in severe cases, also can be deadly. “Over time, the aggregate risk of completed suicide is likely to be much lower with treatment than without treatment,” says Steve Hyman, former director of the National Institute of Mental Health (NIMH). “The larger danger is almost certainly to leave depressed people untreated.” For all the attention rightly being given to antidepressants, “the correct treatment of choice for depression is unchanged: antidepressants or cognitive behavioral therapy,” says Hyman, who is now the provost of Harvard University. (Cognitive behavioral therapy is a type of talk therapy that helps patients identify and change troublesome thought patterns and behaviors.) “The situation reminds us that good medical practice is not to write a prescription and send the person on their way, but to stay connected, monitor them carefully, and educate the patient and the family,” he says. It also underscores the need for other therapeutic options for depression. A large, government-funded study known as STAR*D, which tested currently marketed antidepressant therapies in “real-life” scenarios as opposed to clinical trials sponsored by pharmaceutical companies, made clear the need for new therapies, Hyman notes. In results published over the past two years by lead researcher John Rush of the University of Texas Southwestern Medical Center at Dallas, STAR*D revealed that today’s antidepressants are only moderately effective. Only about 30 percent of people taking the drugs achieved remission, which is defined as the absence of all or most symptoms, and they did so only after an average of 10 weeks on the drugs. Even with the best care, many people suffer significant residual symptoms. “We desperately need better drugs,” Hyman says. The lag time before symptoms subside is particularly troubling: it may take four to six weeks for a patient to feel any benefit. “This is a very worrisome situation when you have severely depressed people, because you have the danger of them committing suicide before the drug takes effect,” says Nobel laureate Paul Greengard, whose Rockefeller University team last summer discovered a protein, p11, that seems to be critically involved in depression and antidepressant action. A Few Leads While the immediate prospects for a better antidepressant pill are bleak, the work of Greengard and others offers a few glimmers of hope. In basic research that for now is still far from clinical applications, Greengard’s group at Rockefeller found intriguing links between p11 levels and depression and is currently investigating the mechanisms by which elevated p11 improves depressive symptoms. It is possible, Greengard says, that p11 may be the key to unraveling the neurochemical changes underlying depression, as well as revealing how modern antidepressants work—information that would pave the way for better drugs. Another glimmer comes from government-initiated studies of ketamine, an anesthetic used in children in most of the world but mostly reserved for use in animals in the United States. NIMH researcher Carlos Zarate and his colleagues reported in 2006 that ketamine, delivered via an intravenous infusion, stopped depression symptoms immediately. Within just two hours, half of the severely depressed people in the small study responded to ketamine with at least a 50 percent decrease in symptoms. By the end of the first day of the seven-day study, 71 percent of subjects met this criterion; by day 7, response had dropped off a bit, to 35 percent of subjects. Ketamine acts on glutamate, an abundant neurotransmitter that plays many roles in neuronal function. The drug is not yet a viable clinical treatment, for several reasons: intravenous infusion is impractical, the effects taper off, and some people in the study experienced side effects such as out-of-body sensations, visual hallucinations of trails of light, and other mild hallucinations during the infusions. The real importance of the study is that it “suggests that it is possible to induce rapid antidepressant effects, in hours or days,” Zarate says. “So we can dismiss the notion that we have to accept this lag of weeks or months that characterizes standard antidepressants.” Inducing such a rapid response consistently and sustaining the response over time is the hurdle now before Zarate, and his team is trying various approaches. First and foremost, they want to understand the mechanisms underlying the rapid effect, using brain imaging to pinpoint the brain areas and track the impact on glutamate signaling. Those clues could then be applied to new drug development. Zarate’s team is also testing ketamine in combination with riluzole, a drug used to treat amyotrophic lateral sclerosis. Riluzole also acts on glutamate signaling, though in different ways, so the idea is to give patients a one-two punch: ketamine first to induce a rapid response, followed by riluzole to sustain the response. Clinical trials are currently under way to test this hypothesis. Another approach is to create a more selective version of ketamine that would minimize side effects. The glutamate receptor, on which ketamine and riluzole act, is a large, complex molecule with many subunits. One of these subunits, called NR2b, is of particular interest, and molecules that block it have been developed in an oral form and tested in humans with head trauma and ischemia (conditions associated with excess glutamate release). Zarate has now begun a clinical trial of an NR2b blocker in depression. Such avenues of research represent “important and exciting leads,” Hyman says. “But they’re miles away from being a treatment.”

depression, suicide, antidepressant, drugs, serotonin, prozac, ssris, treatment, medication, p11, ketamine, glutamate, riluzole